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Three‐dimensional structure of a complex of galanthamine (Nivalin ® ) with acetylcholinesterase from Torpedo californica : Implications for the design of new anti‐Alzheimer drugs
Author(s) -
Bartolucci Cecilia,
Perola Emanuele,
Pilger Christian,
Fels Gregor,
Lamba Doriano
Publication year - 2000
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/1097-0134(20010201)42:2<182::aid-prot50>3.0.co;2-1
Subject(s) - chemistry , acetylcholinesterase , stereochemistry , binding site , torpedo , allosteric regulation , active site , docking (animal) , ligand (biochemistry) , acetylcholine receptor , biochemistry , enzyme , receptor , medicine , nursing
The 3D structure of a complex of the anti‐Alzheimer drug galanthamine with Torpedo californica acetylcholinesterase is reported. Galanthamine, a tertiary alkaloid extracted from several species of Amarylidacae , is so far the only drug that shows a dual activity, being both an acetylcholinesterase inhibitor and an allosteric potentiator of the nicotinic response induced by acetylcholine and competitive agonists. The X‐ray structure, at 2.5Å resolution, shows an unexpected orientation of the ligand within the active site, as well as unusual protein–ligand interactions. The inhibitor binds at the base of the active site gorge, interacting with both the acyl‐binding pocket and the principal quaternary ammonium‐binding site. However, the tertiary amine group of galanthamine does not directly interact with Trp84. A docking study using the program AUTODOCK correctly predicts the orientation of galanthamine in the active site. The docked lowest‐energy structure has a root mean square deviation of 0.5Å with respect to the corresponding crystal structure of the complex. The observed binding mode explains the affinities of a series of structural analogs of galanthamine and provides a rational basis for structure‐based drug design of synthetic derivatives with improved pharmacological properties. Proteins 2001;42:182–191. © 2000 Wiley‐Liss, Inc.